The goal of this Phase 1 SBIR proposal is to identify lead drug candidates from a library of tumor necrosis factor a (TNF-alpha) inhibitors for treating amyotrophic lateral sclerosis (ALS). ALS is a motor neuron disorder that affects tens of thousands of Americans and current drugs display limited efficacy. An unmet need exists for new and effective treatments for ALS. Recent evidence identifies TNF-alpha as a drug target for treating ALS. TNF-a levels are elevated in ALS patient serum and spinal cord of ALS mouse models. The selective TNF-a inhibitor thalidomide improves motor performance and prolongs survival in ALS mice suggesting TNFa as an ALS drug target. Phase 2 Discovery has developed a family of proprietary thiothalidomides that are up to 30-fold more potent in inhibiting TNF-a compared to thalidomide. Thiothalidomides are predicted to be more potent than thalidomide for symptomatic improvement in ALS mice. Phase 2 Discovery will evaluate drug efficacy of thiothalidomides in ALS mice by employing a proprietary ELISA-based biomarker of neuronal damage, cleaved microtubule-associated protein tau (C-tau). Our studies indicate that spinal cord C-tau is an objective biomarker of ALS-associated motor neuron damage and drug efficacy in ALS mice. The efficiency, reliability and specificity of C-tau ELISA for quantifying ALS associated neuropathology allows drug discovery to proceed faster, use fewer animals and reduce costs compared to currently used endpoints. The proposed study will determine the efficacy of TNF-alpha inhibiting thiothalidomides employing rotorod motor performance scores and C-tau biomarker levels in ALS mice. SPECIFIC AIM: Determine the effect of thiothalidomides on rotorod motor performance, spinal cord C-tau levels and spinal cord TNF-alpha levels in ALS mice.